Estrogens are steroid or non-steroid estrogenic hormones, and various substances including not only natural substances but also synthetic substances are known as estrogens (Environmental Health Perceptives, Vol. 61, pp. 97-110 (1985)). Natural human estrogen is 17.beta.-estradiol produced mainly in ovary and this hormone plays an important role in the development of female secondary sexual character, the proliferation of endometrium, the control of sexual functions, the control of metabolism in bone, the control of lipid metabolism, etc. Therefore, when the estrogen in the body is deficient owing to aging or ovary malfunction, there are caused specific medical symptoms such as osteoporosis, menopausal disorders, lipid metabolism abnormality and vasomotor syndrome associated with menopause, atrophic vaginitis, kraurosis vulvae, premenstrual tension syndrome, female hypogonadism, etc. Estrogen supplementation therapy is applied to these diseases. The prophylactic effect of estrogen on fracture due to coronary cardiopathy or osteoporosis has recently been elucidated in postmenopausal women (Annals of Internal Medicine, Vol. 117, pp. 1038-1041 (1992)). Estrogen accelerates gonadotropin inhibition and is used also as a contraceptive in combination with progestogens (e.g. progesterone), other female sex hormones. However, since long-term administration of estrogen produces adverse side effects such as mastodynia, dysfunctional genital bleeding, corpulence, endometrial hyperplasia, endometrioma, mammary cancer, myocardial infarction, thromboembolism, cerebrovascular diseases, etc., a therapeutic agent having a more selective estrogen action is desired American Journal of Medicine, Vol. 94, pp. 646-650 (1993)!.
There have already been reported the following compounds obtained by combining each of various estrogens with a compound having a specific molecular structure which is considered to be rich in affinity for osseous tissue (a compound having affinity for bone) by a covalent bond through a spacer in order to incorporate the estrogen selectively into bone:
1) Compounds obtained by bonding a poly-(malonic acid) derivative as a compound having affinity for bone to the hydroxyl group of a 17.beta.-estradiol derivative or the like by a carbamate linkage (Japanese Patent Unexamined Publication No. 2-36145).
2) Compounds obtained by bonding a bisphosphonic acid derivative as a compound having affinity for bone to the hydroxyl group of 17.beta.-estradiol by an ester linkage or a carbamate linkage (Japanese Patent Application Kohyo No. 6-500777).
3) Compounds obtained by bonding a bisphosphonic acid derivative to the hydroxyl group of a steroid compound such as 17.beta.-estradiol by a carbamate linkage, thiocarbamate linkage or carbonate linkage (Japanese Patent Unexamined Publication No. 4-352795).
4) Compounds obtained by bonding a bisphosphonic acid derivative to the hydroxyl group of a steroid compound such as 17.beta.-estradiol by an ester linkage or a carbamate linkage (Japanese Patent Unexamined Publication No. 5-286993).
5) Specific compounds obtained by bonding a bisphosphonic acid derivative to the hydroxyl group of 17.beta.-estradiol by an ester linkage (Japanese Patent Unexamined Publication No. 6-100576).
6) Compounds obtained by bonding a bisphosphonic acid derivative to the hydroxyl group of 17.beta.-estradiol or the like by an ether linkage (Japanese Patent Unexamined Publication Nos. 5-230086 and 6-329697).
7) Compounds obtained by bonding a bisphosphonic acid derivative to the hydroxyl group of 17.beta.-estradiol or the like by an ether linkage or a carbamate linkage (Japanese Patent Unexamined Publication No. 5-345791).
8) Compounds obtained by bonding a bisphosphonic acid derivative directly to the basic skeleton of an estrogen compound such as a hexestrol derivative or 2-phenylindole derivative through an alkylene group (Japanese Patent Unexamined Publication No. 5-222073).
Of the inventive compounds disclosed in these references, the compounds disclosed in 1) to 5) above are obtained by bonding a compound having affinity for bone to the hydroxyl group of an estrogen compound to form a so-called pro-drug type ester or carbamate, whose ester linkage or carbamate linkage is easily severed by metabolism in a living body. The estrogen compound released in the living body is expected to exhibit its effect in a local osseous tissue. The compounds disclosed in 6) and 7) above are obtained by bonding a compound having affinity for bone to the hydroxyl group of an estrogen compound to form an ether which is hardly decomposed by metabolism in a living body. Even if the whole ether molecule is transferred to an objective osseous tissue, it has a weakened effect as estrogen because at least one of the two important hydroxyl groups for exhibition of estrogen activity is blocked. Thus, it is considered that such compounds have inhibitory effect on bone resorption as so-called bisphosphonic acid derivatives. In addition, the compounds disclosed in 8) above are obtained by bonding a compound having affinity for bone directly to the basic skeleton of an estrogen compound through a spacer and hence retain the two important hydroxyl groups for exhibition of estrogen activity unlike the compounds disclosed in 1) to 7) above. However, the exhibition of estrogen action by such a bonding method has been not yet sufficient.
As compounds having affinity for bone, bisacylphosphonic acid derivatives Pharmaceutical Research, Vol. 9, 143-148 (1992)!, iminobismethylenebisphosphonic acid derivatives Japanese Patent Unexamined Publication No. 6-298779! and tartronic acid derivatives WO9409770 and WO9410127! are known as background art in addition to the above-mentioned poly(malonic acid) derivatives and bisphosphonic acid derivatives. However, no compound obtained by bonding any of such derivatives to estrogen is described in these references.
The present invention is intended to provide a therapeutic agent and a prophylactic agent, which contains as an active ingredient a novel estrogen derivative having a higher selectivity for osseous tissue than for other organs such as genital organs, etc. is highly effective against diseases due to estrogen deficiency by virtue of the enhancement or prolongation of the effect of the derivative by its accumulation in osseous tissue, and has less adverse side effect.